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Journal of Global Antimicrobial... Sep 2021The incidence of infections due to Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MABS) is increasing worldwide. Current antimycobacterial agents are not... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The incidence of infections due to Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MABS) is increasing worldwide. Current antimycobacterial agents are not sufficiently effective against nontuberculous mycobacteria (NTM) and there is a need for new drugs. This study aimed to estimate the overall in vitro activity of clofazimine (CFZ) against MAC and MABS clinical isolates.
METHODS
We systematically searched four databases up to 1 March 2020 to identify relevant studies. Studies were included if they used the Clinical and Laboratory Standards Institute (CLSI) criteria for drug susceptibility testing (DST). We assessed the pooled in vitro CFZ resistance rate in MAC and MABS clinical isolates using a random- effects model. Sources of heterogeneity were evaluated using Cochran's Q and the I statistic. Potential for publication bias was explored using Begg's and Egger's tests. All analyses were conducted using Stata 14.0.
RESULTS
A total of 20 publications (11 reports for MAC and 15 for MABS) were included. The pooled rates of in vitro resistance to CFZ in clinical isolates of MAC and MABS were 9.0% [95% confidence interval (CI) 3.0-17.0%] and 16.0% (95% CI 4.0-34.0%), respectively. There was no evidence of publication bias.
CONCLUSION
This study reports the frequency of CFZ resistance in clinical isolates of MAC and MABS. According to the results, establishing accurate DST methods for detecting CFZ resistance, performing DST for all NTM isolates to provide effective treatment, and continuous monitoring of drug resistance are suggested for the prevention and control of CFZ-resistant NTM.
Topics: Clofazimine; Humans; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium tuberculosis
PubMed: 34153525
DOI: 10.1016/j.jgar.2021.06.002 -
Respiratory Medicine Oct 2021The lack of reliable predictors for the treatment response complicates decisions to initiate treatment in patients with Mycobacterium abscessus complex pulmonary disease...
INTRODUCTION
The lack of reliable predictors for the treatment response complicates decisions to initiate treatment in patients with Mycobacterium abscessus complex pulmonary disease (MABC-PD). We aimed to investigate whether baseline radiographic disease severity is associated with treatment outcome in MABC-PD.
METHOD
We retrospectively analyzed 101 patients with MABC-PD (54 with M. abscessus-PD and 47 with M. massiliense-PD) treated in a tertiary referral hospital between January 2006 and December 2019. Using chest computed tomography images, baseline radiographic disease severity was quantitatively scored according to five categories of radiographic lesions (bronchiectasis, bronchiolitis, cavities, nodules, and consolidation).
RESULTS
Treatment success was achieved in 53.7% of patients with M. abscessus-PD and 85.1% of patients with M. massiliense-PD. Higher overall scores for baseline radiographic disease severity were associated with treatment failure in patients with M. massiliense-PD (aOR 1.35, 95% CI 1.02-1.79 for each 1-point increase in severity score), as well as in patients with M. abscessus-PD (aOR 1.15, 95% CI 1.00-1.33). This was particularly prominent in patients with overall severity score of ≥14 (aOR 31.16, 95% CI 1.12-868.95 for M. massiliense-PD and aOR 3.55, 95% CI 1.01-12.45 for M. abscessus-PD). Among variable radiographic abnormalities, the score for cavitary lesion severity was associated with treatment failure in patients with M. abscessus-PD (aOR 1.26, 95% CI 1.01-1.56), but not in patients with M. massiliense-PD.
CONCLUSIONS
Given the association between baseline radiographic disease severity and treatment outcome, initiating treatment should be actively considered before significant progression of radiographic lesions in patients with MABC-PD.
Topics: Aged; Amikacin; Anti-Bacterial Agents; Cefoxitin; Drug Therapy, Combination; Female; Humans; Imipenem; Infusions, Intravenous; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Pneumonia, Bacterial; Radiography, Thoracic; Retrospective Studies; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 34380092
DOI: 10.1016/j.rmed.2021.106549 -
Cell Chemical Biology May 2022Mycobacterium abscessus is an emerging and difficult-to-manage mycobacterial species that exhibits smooth (S) or rough (R) morphotypes. Disruption of glycopeptidolipid...
Mycobacterium abscessus is an emerging and difficult-to-manage mycobacterial species that exhibits smooth (S) or rough (R) morphotypes. Disruption of glycopeptidolipid (GPL) production results in transition from S to R and severe lung disease. A structure-activity relationship study was undertaken to decipher the role of GPL glycosylation in morphotype transition and pathogenesis. Deletion of gtf3 uncovered the prominent role of the extra rhamnose in enhancing mannose receptor-mediated internalization of M. abscessus by macrophages. In contrast, the absence of the 6-deoxy-talose and the first rhamnose in mutants lacking gtf1 and gtf2, respectively, affected M abscessus phagocytosis but also resulted in the S-to-R transition. Strikingly, gtf1 and gtf2 mutants displayed a strong propensity to form cords and abscesses in zebrafish, leading to robust and lethal infection. Together, these results underscore the importance and differential contribution of GPL monosaccharides in promoting virulence and infection outcomes.
Topics: Animals; Glycosylation; Mycobacterium abscessus; Rhamnose; Surface Properties; Virulence; Zebrafish
PubMed: 35358417
DOI: 10.1016/j.chembiol.2022.03.008 -
Journal of the Formosan Medical... Jun 2020Nontuberculous mycobacterial infections and colonization are becoming more prevalent worldwide. Mycobacterium abscessus complex (MABC) is one of the predominant... (Review)
Review
Nontuberculous mycobacterial infections and colonization are becoming more prevalent worldwide. Mycobacterium abscessus complex (MABC) is one of the predominant pathogens capable of a wide spectrum of infections, with 50% of infections involving the lungs. The decision to commence treatment is determined according to the severity of the disease, risk of progressive disease, presence of comorbidities, and goals of treatment. MABC is resistant to standard antituberculous agents and has variable drug susceptibility across different geographical locations, therefore, antibiotic susceptibility testing of all clinically significant isolates is crucial for selecting a treatment strategy. Pulmonary infections due to MABC is difficult to cure using the currently recommended regimens from the American Thoracic Society and British Thoracic Society. Macrolides are the cornerstone of treatment, but the efficacy of macrolide-based chemotherapy may be compromised by resistance. Despite the introduction of new drugs for treatment, treatment outcomes remain unsatisfactory. The combination of surgical resection of limited lung disease regions with a multidrug, macrolide-based therapy offers the optimal chance of achieving clinical cure of the disease. This review focuses on medical treatment of MABC-lung disease and the efficacy of new agents, such as clofazimine, amikacin inhalation therapy, tigecycline and linezolid, for treating MABC-lung disease.
Topics: Anti-Bacterial Agents; Humans; Lung Diseases; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus
PubMed: 32527504
DOI: 10.1016/j.jfma.2020.05.028 -
PLoS Pathogens Aug 2022ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake...
ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.
Topics: Animals; Bacterial Proteins; Mice; Mycobacterium; Mycobacterium abscessus; Mycobacterium marinum; Mycobacterium tuberculosis; Type VII Secretion Systems; Zebrafish
PubMed: 35960766
DOI: 10.1371/journal.ppat.1010771 -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Mycobacterium abscessus; Scalp; Central America; Skin Transplantation; Hair
PubMed: 38110217
DOI: 10.1503/cmaj.230794-f -
Antimicrobial Agents and Chemotherapy Jul 2023Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of...
Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
Topics: Humans; Mycobacterium abscessus; Azithromycin; Anti-Bacterial Agents; Amikacin; Mycobacterium Infections, Nontuberculous; Drug Interactions; Microbial Sensitivity Tests
PubMed: 37278639
DOI: 10.1128/aac.00090-23 -
Microbiology Spectrum Dec 2022Mycobacterium abscessus is an emerging pathogen that critically depends on iron for growth and pathogenesis. The acquisition of iron in Mycobacterium tuberculosis is...
Mycobacterium abscessus is an emerging pathogen that critically depends on iron for growth and pathogenesis. The acquisition of iron in Mycobacterium tuberculosis is governed by siderophores called mycobactins, synthesized by the gene cluster, but the role of this gene cluster in the adaption of M. abscessus to iron limitation is not characterized. We identified an M. abscessus Tn_mutant with interruption of the gene (), a central component of mycobactin biosynthesis. We tested this isolate growth characteristic, dependency on supplements, and transcriptomic response, comparing it to the response of wild-type (WT) bacteria in iron-limiting conditions. We also compare the structure of the gene cluster across several mycobacteria. The Tn_ mutant had a substantial, but not absolute, growth defect, which was more substantial in iron-limited media. Supplementation with mycobactin-J, hemin, blood, and surprisingly, albumin, salvaged the poor growth. Similarly, secreted mature (carboxy)-mycobactins from WT bacteria rescued the Tn_ mutant during iron deprivation. The transcriptomic response of the Tn mutant involved the upregulation of genes known to be implicated in iron homeostasis and was comparable to that of WT bacteria grown in iron-limiting conditions. Interestingly, the response was not identical to the response of M. tuberculosis to iron limitation. The gene cluster and mycobactins play important roles in the physiology of M. abscessus. (Carboxy)-mycobactin is secreted from WT bacteria and can serve as "public good." The role of several iron-homeostasis related genes (like ) may differ between M. abscessus and Mtb. Mycobacterium abscessus is an emerging human pathogen belonging to the nontuberculous mycobacteria (NTM) family, causing severe pulmonary disease in compromised individuals. How this bacterium acquires iron is poorly understood. Here, we provide the first characterization of the role(s) the gene required for the biosynthesis of siderophore mycobactin in M. abscessus. We show that the gene s required for growth during iron deprivation and can be compensated by several supplements, including, surprisingly, albumin. We also show the transcriptomic response of the -mutant is comparable to the response of the parental strain to iron starvation and seems different from the response of M. tuberculosis. These results indicate the importance of studying mycobactin in M. abscessus and NTM strains. Understanding this pathway is central to understanding the acquisition of iron within hosts and its role in pathogenesis, which in turn may facilitate the development of antimycobacterial therapeutics.
Topics: Humans; Mycobacterium abscessus; Mycobacterium tuberculosis; Iron; Siderophores; Tuberculosis
PubMed: 36321891
DOI: 10.1128/spectrum.02623-22 -
International Journal of Molecular... Feb 2023is an opportunistic pathogen that mainly colonizes and infects cystic fibrosis patients' lungs. is naturally resistant to many antibiotics such as rifamycin,... (Review)
Review
is an opportunistic pathogen that mainly colonizes and infects cystic fibrosis patients' lungs. is naturally resistant to many antibiotics such as rifamycin, tetracyclines and β-lactams. The current therapeutic regimens are not very effective and are mostly based on repurposed drugs used against infections. Thus, new approaches and novel strategies are urgently needed. This review aims to provide an overview of the latest ongoing findings to fight infections by analyzing emerging and alternative treatments, novel drug delivery strategies, and innovative molecules.
Topics: Humans; Cystic Fibrosis; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous; beta-Lactams; Mycobacterium abscessus; Microbial Sensitivity Tests
PubMed: 36902066
DOI: 10.3390/ijms24054635 -
The Journal of Antimicrobial... Jul 2020Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%....
BACKGROUND
Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.
OBJECTIVES
To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients.
METHODS
We infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5 mg doses, by inhalation, or untreated, for 28 days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time-kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients.
RESULTS
Inhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients.
CONCLUSIONS
Inhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.
Topics: Animals; Anti-Bacterial Agents; Humans; Lung Diseases; Mice; Mice, Knockout; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Tigecycline
PubMed: 32294173
DOI: 10.1093/jac/dkaa110